Periodic Reporting for period 1 - TheRaCil (Therapies for Renal Ciliopathies)
Período documentado: 2023-07-01 hasta 2024-12-31
Many cells feature primary cilia on their surface, which are microtubule-based antennae crucial for controlling essential signaling processes during development and tissue maintenance. Dysfunctional cilia lead to ciliopathies, rare genetic disorders with diverse symptoms. A common morbidity associated with ciliopathies include chronic kidney disease (CKD) and end-stage kidney disease (ESKD), necessitating dialysis and transplantation. The EU-funded TheRaCil project, leveraging European patient databases, biocollections, robust preclinical models, and AI-based tools, aims to enhance diagnosis, prognosis, and treatment options for pediatric renal ciliopathies (RCs). The research includes repurposing therapeutic molecules targeting disease-associated pathways and the use of antisense oligonucleotides to directly target kidney gene variants. Additionally, researchers will identify disease modifier genes, biomarkers, and refine patient stratification for improved treatment eligibility criteria.
The TheRaCil project has made significant progress in developing tailored therapies for pediatric RCs. A comprehensive data integration framework was established, including a common data model (CDM) for ciliopathies. Multi-omics analyses identified disrupted signaling pathways and disease signatures, while essential tools such as knockout cell lines and proximity labelling constructs were developed for comprehensive assessments of disease-associated ciliary defects. Additionally, the first version of a machine learning-based prediction model was created to identify key molecular mechanisms and therapeutic targets.
Robust in vitro and in vivo models of RCs have been developed. Preclinical studies validated lead molecules for therapeutic approaches in several NPH models, demonstrating the efficacy of prostaglandin E2 receptor agonists in restoring ciliogenesis and reducing disease phenotypes. Recent preprints and recently obtained results broaden the potential beneficial effects of these compounds to different NPH genetic backgrounds. ASO-mediated exon skipping therapies targeting CEP290 gene variants showed first promising results in human cells as well as in a mouse model. The project also made progress in developing risk prediction tools for CKD and ESKD, with urinary DKK3 levels validated as a biomarker of kidney disease severity. Additionally, a survey on barriers to access genetic testing for kidney diseases has been performed, highlighting key challenges and opportunities for improving diagnostic access.
Robust in vitro and in vivo models of RCs have been developed. Preclinical studies validated lead molecules for therapeutic approaches in several NPH models, demonstrating the efficacy of prostaglandin E2 receptor agonists in restoring ciliogenesis and reducing disease phenotypes. Recent preprints and recently obtained results broaden the potential beneficial effects of these compounds to different NPH genetic backgrounds. ASO-mediated exon skipping therapies targeting CEP290 gene variants showed first promising results in human cells as well as in a mouse model. The project also made progress in developing risk prediction tools for CKD and ESKD, with urinary DKK3 levels validated as a biomarker of kidney disease severity. Additionally, a survey on barriers to access genetic testing for kidney diseases has been performed, highlighting key challenges and opportunities for improving diagnostic access.
Precision medicine approaches for pediatric renal ciliopathies have two primary limitations: 1) Disease heterogeneity makes it crucial to categorize patients based on their pathophysiological features and molecular signatures. The challenge lies in identifying shared targetable pathways associated with various onsets of CKD. 2) The identification of CKD at-risk patients is necessary so that they can be eligible for treatment before reaching ESKD. To meet these challenges, the TheRaCil consortium is making progress on:
• Clustering pediatric RC patients
• Identifying markers and modifiers of disease progression
• Identifying shared targetable pathological pathways
• Developing candidate therapeutic approaches suitable for clinical use
• Defining criteria for clinical trials
The TheRaCil project has already achieved several results that push the boundaries of current knowledge and practice. One of the key achievements is the validation of urinary DKK3 levels as a biomarker of kidney disease severity in renal ciliopathies, which has been published and provides a valuable tool for assessing disease progression. Additionally, preprints on EP2 agonists reveal their therapeutic potential across NPH genetic backgrounds, demonstrating efficacy in restoring ciliogenesis and reducing disease phenotypes.
The project has also made significant progress in developing Patient Reported Outcome Measures (PROMs) for ARPKD, NPH, and BBS, which will be essential for setting up future clinical trials for renal ciliopathies. These PROMs are being developed with input from patients, caregivers, and professionals to ensure they reflect patient needs and priorities.
To ensure further uptake and success, additional research is needed to validate the identified disease pathways and to design therapeutic approaches targeting those pathways. Access to markets and finance, commercialization support, and a supportive regulatory and standardization framework will be crucial for translating these findings into clinical applications. Collaboration with industry partners and regulatory bodies will be essential to navigate the complex landscape of drug development and approval especially in the field of pediatric disorders. Progress on Patient Reported Outcome Measures (PROMs) in ARPKD, NPH, and BBS, though not yet finalized, will be essential for setting up future clinical trials for renal ciliopathies.
• Clustering pediatric RC patients
• Identifying markers and modifiers of disease progression
• Identifying shared targetable pathological pathways
• Developing candidate therapeutic approaches suitable for clinical use
• Defining criteria for clinical trials
The TheRaCil project has already achieved several results that push the boundaries of current knowledge and practice. One of the key achievements is the validation of urinary DKK3 levels as a biomarker of kidney disease severity in renal ciliopathies, which has been published and provides a valuable tool for assessing disease progression. Additionally, preprints on EP2 agonists reveal their therapeutic potential across NPH genetic backgrounds, demonstrating efficacy in restoring ciliogenesis and reducing disease phenotypes.
The project has also made significant progress in developing Patient Reported Outcome Measures (PROMs) for ARPKD, NPH, and BBS, which will be essential for setting up future clinical trials for renal ciliopathies. These PROMs are being developed with input from patients, caregivers, and professionals to ensure they reflect patient needs and priorities.
To ensure further uptake and success, additional research is needed to validate the identified disease pathways and to design therapeutic approaches targeting those pathways. Access to markets and finance, commercialization support, and a supportive regulatory and standardization framework will be crucial for translating these findings into clinical applications. Collaboration with industry partners and regulatory bodies will be essential to navigate the complex landscape of drug development and approval especially in the field of pediatric disorders. Progress on Patient Reported Outcome Measures (PROMs) in ARPKD, NPH, and BBS, though not yet finalized, will be essential for setting up future clinical trials for renal ciliopathies.